CLINICAL/THERAPEUTIC APPROACHES TO THREE SPECIFIC CARDIOMYOPAHIES:

MYOCARDITIS, AMYLOIDOSIS, AND NON-COMPACTION

G. William Dec, MD, FACCMassachusetts General Hospital

Harvard Medical School American College of Cardiology

New York Cardiovascular Symposium December 9 , 2017

Disclosures: None

HISTOPATHOLOGY OF ACUTE MYOCARDITIS

Myocarditis is a pathologic diagnosis made by endomyocardial biopsy, at the time of cardiac explantation, LVAD placement or at autopsy. It is histologically characterized by an inflammatory cellular infiltrate

(lymphocytic, eosinophilic, granulomatous) that is associated with myocyte necrosis or degeneration (Dallas criteria).

ACUTE LYMPHOCYTIC MYOCARDITISCLINICAL MANIFESTATIONS

Asymptomatic ECG abnormalities Ventricular arrhythmias Myocardial infarction mimicry [parvovirus B19] Acute dilated cardiomyopathy Cardiogenic shock [fulminant]

DIAGNOSTIC APPROACH TO SUSPECTED MYOCARDITIS

Heymans S, et al. J Am Coll Cardiol 2016;68:2348-64.

Unexplained Acute DCM

Hemodynamically Unstable:Inotrope/ MCSHeart Block: Mobitz 2 or higherVentricular Tachyarrhythmias

Failure to Respond to Medical Rx in 2 wks

Endomyocardial BiopsyI/LOE B

CardiacMRI

2B/LOE C

Hemodynamically Stable

NYHA I/II/III

CardiacMRI

2A/LOE B

Biomarkers

CARDIAC MR IMAGING IN SUSPECTED MYOCARDITIS

THE MYO-RACER TRIAL

Lurz P, et al. J Am Coll Cardiol 2016;67:1800-11.

Acute Symptoms Chronic Symptoms

129 patients underwent native T1 imaging, calculation of extracellular volume fraction (ECV), and T2 mapping

NATURAL HISTORY OF LYMPHOCYTIC AND GIANT CELL MYOCARDITIS

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LYMPHOCYTIC MYOCARDITISCONVENTIONAL TREATMENT

Avoidance of strenuous exercise (3-6 months)

ACE inhibitors, beta-blockers, spironolactone per ACC/AHA/HFSA heart failure practice guidelines to treat HF symptoms and promote favorable LV remodeling

ICD for persistent LV dysfunction on GDMT

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Baseline Week 28 Week 52

NIH MYOCARDITIS TREATMENT TRIAL

CP977755-8

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ControlImmunosuppression [prednisone/AZA]

Mason JW, et al. NEJM 1995;333:269-75.

IMMUNOSUPPRESSIVE THERAPY IN VIRUS-NEGATIVE INFLAMMATORY CARDIOMYOPATHY

TIMIC TRIAL RESULTS

Frustaci A, et al Eur Heart J 2009;30:1995-2002.

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Baseline Baseline6 Month 6 Month

Immunosuppression Control

Change in LVEF by Treatment Group

85 pts with myocarditis, symptoms > 6 months, LVEF < 45%

PCR negative [for adenovirus, enterovirus, HSV, influenza, CMV]

Randomized to medical therapy +/- prednisone and azathioprine for 6 monthsL

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SURVIVAL IN GIANT CELL MYOCARDITIS TREATED WITH IMMUNOSUPPRESSIVE THERAPY

Kandolin R,et al. Circulation HF 2013;6:15-22.

26 patients biopsy-positive for GCMMean LVEF: 34% 8%

Immunosuppression:Pred + AZA + Cyclo (65%)Prednisone+ AZA (15%)Pred +Cyclo+ MMF (8%)

MYOCARDITIS: DIAGNOSIS AND TREATMENT 2017

Cardiac MRI is most helpful initial diagnostic study RV biopsy is rarely indicated for suspected lymphocytic

myocarditis but is essential when eosinophilic or giant cell myocarditis is suspected

Steroid therapy is indicated and effective for eosinophilic myocarditis

Immunosuppression (steroids & cytolytics) is useful for giant cell myocarditis and myocarditis associated with known autoimmune disorders (lupus, RA)*

Immunosuppression may be considered for infection-negative lymphocytic myocarditis on an individual basis*

*Caforio A, et al. Eur Heart J 2013;34:2636-48.

TWO PRINCIPAL FORMS OF CARDIAC AMYLOIDOSISAL ATTR

Wild type Mutant

Light chain amyloidosis

Transthyretin amyloidosis

CLASSIC ECG PATTERN IN CARDIAC AMYLOIDOSIS

Pseudoinfarction pattern about 50% in AL

Low voltage 50% in AL

Low voltage 25% in ATTR

Liu et al. Circ Cardiovasc Imaging 2013;6:1066-72.

ECHO STRAIN DIFFERENTIATION FROM OTHERCAUSES OF CONCENTRIC REMODELING

APICAL TO BASAL GRADIENT > 2.1

CMR WITH LGE IDENTIFIES CARDIAC AMYLOIDOSIS WITH A HIGH DEGREE OF ACCURACY

Reference Sensitivity Specificity PPV NPV

Vogelsberg et al., JACC 2008 80% 94% 92% 85%

Ruberg et al. Am J Cardiol2009

86% 86% 95% 67%

Austin et al., JACC CVI 2009 88% 90% 88% 90%

Average 85% 90% 92% 81%

CARDIAC BIOMARKER STAGING IN AL AMYLOIDOSIS

Kumar S et al. J. Clinical Oncology 2012;30:989-995

Risk factors: 1 point each forscore 0-3 Stage 1-4

FLC 180 mg/L

cTnT 0.025 mcg/L

NT-ProBNP 1,800 ng/L

DIAGNOSTIC APPROACH TO SUSPECTEDCARDIAC AMYLOIDOSIS

Echocardiogram with strain imaging Cardiac MRI to more definitively identify amyloid vs. non-

amyloid causes of unexplained LVH

1. AL evaluation-- Serum free light chain assay (kappa/lambda ratio)--Serum and urine immunofixation electrophoresis --NOT SPEP or UPEP

2. TTR evaluation (particularly in older patients)-- Pyrophosphate scan-- Genotyping (wild type or variant/mutant)

3. BNP or nT-pro-BNP and troponin I/T4. Cardiac biopsy in equivocal cases

Immunohistochemistry or mass spectrometry

MANAGING THE HEART IN AL AMYLOIDOSIS

Sudden death PEA, ventricular arrhythmias, and embolism Intracardiac thrombus as high as 35% Controversial value of cardioverter-defibrillator

Atrial arrhythmias Beta-blockers & calcium channel blockers poorly tolerated Digoxin has a bad reputation, but can actually be of value Amiodarone is often the only medical option Anticoagulation

AV block Pacing for AV block and/or chronotropic incompetence

Heart Failure Diuretics are mainstay of therapy

SURVIVAL IN AL AMYLOID CARDIOMYOPATHY BY TREATMENT

Sperry B, et al. J Am Coll Cardiol 2016;67:2941-7.

N= 112

Bortezomib+ Dexamethasone + Alkylating Agent

WILD TYPE TTR AMYLOID (ATTRw)

Due to deposition of wild-type transthyretin Senile cardiac amyloid A disease of white elderly males (median age: 72) Bilateral carpal tunnel syndrome is common More indolent, prognosis ~ 25% pts > 80 yrs have wild type TTR amyloid deposits

in myocardium at autopsy ? % of clinical HF-pEF cases

Tanskanen Ann Med. 2008;40(3) :232-9Cornwell Am J Med. 1983;75(4): 618-23

ROLE OF TECHNITIUM PYROPHOSPHATE IN SUSPECTED CARDIAC AMYLOIDOSIS

Falk R, et al. JACC 2016;68:1323-40.

ATTR AL

EXTRACELLULAR VOLUME BY MRI AND OUTCOME IN ATTR

Martinez-Naharro A, et al. J Am Coll Cardiol 2017;70:466-77.

SURVIVAL FOR WILD TYPE ATTR AMYLOIDOSIS

Connor LH, et al. Circulation 2016;133:282-90Castano A. et al JAMA Cardiol 2016;1:880-9.

N=121; mean age 75 (62-88)Mean LVEF: 50%

Natural history Survival by PPY Uptake

Emerging therapies focus on 3 general mechanisms: Stabilization of the TTR complex [Tafamidis and

tolcapone ] Silencing expression of the TTR gene [RNAi and

antisense therapies] Removal of amyloid plaques from diseased tissue

by targeting serum amyloid protein (SAP) [Humanized monoclonal antibodies: NEOD001]

Heart (AL) and/or heart-liver transplantation (WTTR) may be appropriate in carefully selected patients

ATTR THERAPY: STABILIZERS, SILENCERS, AND SERUM AMYLOID PROTEIN DEPLETION

LEFT VENTRICULAR NONCOMPACTION

Hussein A, et al. J Am Coll Cardiol 2015;66:578-85.

LVNC results from intrauterine arrest of compaction of the loose network of primordial fetal myocardium NC/C ratio > 2.0-2.3Hypertrabeculation + LV dysfunction = cardiomyopathyFamilial: 18%-50%Increased trabeculation is a common finding during pregnancy, black individuals, CKD, and athletes and often regresses

LEFT VENTRICULAR NONCOMPACTION

Hussein A, et al. J Am Coll Cardiol 2015;66:578-85.

Normal LVNC LVNC

LEFT VENTRICULAR NONCOMPACTION CLINICAL PRESENTATIONS

Dyspnea: 60% Chest pain: 15% Palpitations: 18% Syncope: 9% Stroke: 3%

Asymptomatic: 15%-18%

NYHA class III/IV heart failure: 31%

Bhatia NL, et al. J Cardiac Fail 2011;17:771-8

NATURAL HISTORY OF LEFT VENTRICULAR NONCOMPACTION

Lofiego C, et al. Heart 2007;93:65-71

SCD:70%

Peters F, et al. J Card Failure 2014;20:709-15.

LEFT VENTRICULAR NONCOMPACTIONMAJOR COMPLICATIONS

Heart Failure Conventional pharmacological agents: beta-blockers,

ARB or ACE-I, aldosterone antagonist Thromboembolic Complications

Anticoagulation for documented thrombus, atrial fibrillation or prior TIA/CVA

? Dense trabeculations Atrial Arrhythmias

Atrial fibrillation in 10-20% Ventricular Arrhythmias/Sudden Death

ICD for LVEF < 35%

CLINICAL/THERAPEUTIC APPROACHES TO THREE SPECIFIC CARDIOMYOPAHIES:MYOCARDITIS, AMYLOIDOSIS, AND NON-COMPACTION HISTOPATHOLOGY OF ACUTE MYOCARDITISACUTE LYMPHOCYTIC MYOCARDITISCLINICAL MANIFESTATIONSDIAGNOSTIC APPROACH TO SUSPECTED MYOCARDITIS CARDIAC MR IMAGING IN SUSPECTED MYOCARDITISTHE MYO-RACER TRIALSlide Number 6LYMPHOCYTIC MYOCARDITIS CONVENTIONAL TREATMENTNIH MYOCARDITIS TREATMENT TRIALIMMUNOSUPPRESSIVE THERAPY IN VIRUS-NEGATIVE INFLAMMATORY CARDIOMYOPATHYTIMIC TRIAL RESULTS Slide Number 10MYOCARDITIS: DIAGNOSIS AND TREATMENT 2017Slide Number 12Classic ECG Pattern IN CARDIAC AMYLOIDOSISECHO STRAIN DIFFERENTIATION FROM OTHERCAUSES OF CONCENTRIC REMODELINGSlide Number 15Cardiac Biomarker Staging in al amyloidosisDIAGNOSTIC APPROACH TO SUSPECTEDCARDIAC AMYLOIDOSIS Managing the Heart in AL AmyloidosisSURVIVAL IN AL AMYLOID CARDIOMYOPATHY BY TREATMENTWild type TTR amyloid (ATTRw)ROLE OF TECHNITIUM PYROPHOSPHATE IN SUSPECTED CARDIAC AMYLOIDOSISEXTRACELLULAR VOLUME BY MRI AND OUTCOME IN ATTRSURVIVAL FOR WILD TYPE ATTR AMYLOIDOSISSlide Number 24LEFT VENTRICULAR NONCOMPACTION LEFT VENTRICULAR NONCOMPACTION LEFT VENTRICULAR NONCOMPACTION CLINICAL PRESENTATIONSNATURAL HISTORY OF LEFT VENTRICULAR NONCOMPACTION LEFT VENTRICULAR NONCOMPACTION MAJOR COMPLICATIONS